Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes

Lin T. Guey, Montserrat García-Closas, Cristiane Murta-Nascimento, Josep Lloreta, Laia Palencia, Manolis Kogevinas, Nathaniel Rothman, Gemma Vellalta, M. Luz Calle, Gaëlle Marenne, Adonina Tardón, Alfredo Carrato, Reina García-Closas, Consol Serra, Debra T. Silverman, Stephen Chanock, Francisco X. Real, Núria Malats

Research output: Contribution to journalArticle

Abstract

Background: Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes. Objective: To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity. Design, setting, and participants: The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n = 1149). Measurements: A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n = 586), high-grade nonmuscle invasive (n = 219), and muscle invasive (n = 246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested. Results and limitations: Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate. Conclusions: These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.

Original languageEnglish (US)
Pages (from-to)283-292
Number of pages10
JournalEuropean Urology
Volume57
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

Fingerprint

Genetic Predisposition to Disease
Urinary Bladder Neoplasms
Muscles
Neoplasms
Genetic Loci
Acetylation
Spain
Vascular Endothelial Growth Factor A
Genes
Single Nucleotide Polymorphism
Case-Control Studies
Urinary Bladder
Alleles
Odds Ratio
Genotype
Confidence Intervals
Pathology
Carcinoma

Keywords

  • Genetic polymorphism
  • Heterogeneity
  • Pathologic characteristics
  • Tumour subphenotypes
  • Urinary bladder cancer

ASJC Scopus subject areas

  • Urology

Cite this

Guey, L. T., García-Closas, M., Murta-Nascimento, C., Lloreta, J., Palencia, L., Kogevinas, M., ... Malats, N. (2010). Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes. European Urology, 57(2), 283-292. https://doi.org/10.1016/j.eururo.2009.08.001

Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes. / Guey, Lin T.; García-Closas, Montserrat; Murta-Nascimento, Cristiane; Lloreta, Josep; Palencia, Laia; Kogevinas, Manolis; Rothman, Nathaniel; Vellalta, Gemma; Calle, M. Luz; Marenne, Gaëlle; Tardón, Adonina; Carrato, Alfredo; García-Closas, Reina; Serra, Consol; Silverman, Debra T.; Chanock, Stephen; Real, Francisco X.; Malats, Núria.

In: European Urology, Vol. 57, No. 2, 02.2010, p. 283-292.

Research output: Contribution to journalArticle

Guey, LT, García-Closas, M, Murta-Nascimento, C, Lloreta, J, Palencia, L, Kogevinas, M, Rothman, N, Vellalta, G, Calle, ML, Marenne, G, Tardón, A, Carrato, A, García-Closas, R, Serra, C, Silverman, DT, Chanock, S, Real, FX & Malats, N 2010, 'Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes', European Urology, vol. 57, no. 2, pp. 283-292. https://doi.org/10.1016/j.eururo.2009.08.001
Guey LT, García-Closas M, Murta-Nascimento C, Lloreta J, Palencia L, Kogevinas M et al. Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes. European Urology. 2010 Feb;57(2):283-292. https://doi.org/10.1016/j.eururo.2009.08.001
Guey, Lin T. ; García-Closas, Montserrat ; Murta-Nascimento, Cristiane ; Lloreta, Josep ; Palencia, Laia ; Kogevinas, Manolis ; Rothman, Nathaniel ; Vellalta, Gemma ; Calle, M. Luz ; Marenne, Gaëlle ; Tardón, Adonina ; Carrato, Alfredo ; García-Closas, Reina ; Serra, Consol ; Silverman, Debra T. ; Chanock, Stephen ; Real, Francisco X. ; Malats, Núria. / Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes. In: European Urology. 2010 ; Vol. 57, No. 2. pp. 283-292.
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AU - Guey, Lin T.

AU - García-Closas, Montserrat

AU - Murta-Nascimento, Cristiane

AU - Lloreta, Josep

AU - Palencia, Laia

AU - Kogevinas, Manolis

AU - Rothman, Nathaniel

AU - Vellalta, Gemma

AU - Calle, M. Luz

AU - Marenne, Gaëlle

AU - Tardón, Adonina

AU - Carrato, Alfredo

AU - García-Closas, Reina

AU - Serra, Consol

AU - Silverman, Debra T.

AU - Chanock, Stephen

AU - Real, Francisco X.

AU - Malats, Núria

PY - 2010/2

Y1 - 2010/2

N2 - Background: Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes. Objective: To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity. Design, setting, and participants: The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n = 1149). Measurements: A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n = 586), high-grade nonmuscle invasive (n = 219), and muscle invasive (n = 246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested. Results and limitations: Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate. Conclusions: These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.

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KW - Heterogeneity

KW - Pathologic characteristics

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KW - Urinary bladder cancer

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